Update: Subcutaneous Interleukin-2

Interleukin-2 has been studied for over a decade as a potential adjunct in
the treatment of HIV -- and we have reported on the equivocal results of those clinical trials.
Widespread adoption of IL-2 as an adjunct to antiretroviral therapy has been stalled for a
number of reasons: it is not available in oral form, many patients find the side effects
intolerable, and there has been concern about this cytokine's stimulatory effects on HIV
replication. On the other hand, IL-2 is the only substance currently under study that stimulates
CD4 cell production.

The role of IL-2 in treating patients with HIV infection remains to be
determined, but because of the cytokine's potent immunomodulatory properties, research
with this substance has continued. A recent multicenter study that added subcutaneous
injections of IL-2 to a variety of HAART regimens suggests that routine use of this
immune-system stimulator may be approaching. Davey et al. recruited 82 patients and
randomized them to receive either HAART alone or HAART in combination with subcutaneous
IL-2. The study did not include a placebo arm. Relevant baseline characteristics were
as follows: absolute CD4 counts between 200-500 cells/mm3, no history of IL-2 use,
no AIDS-defining events, and viral load less than 10,000 copies/mL.

Thirty-nine of these patients were randomized to receive 7.5 million units
of IL-2 twice daily for five-day periods every eight weeks, in addition to HAART.
Forty-three patients were randomized to HAART alone. Patients were followed for approximately
one year, allowing for six treatment cycles. Broad latitude was allowed for HAART regimens;
the study design stipulated that patients "were required to be receiving a stable regimen
of either standard-of-care approved multidrug therapy or experimental antiretroviral agents
available through expanded access for at least two weeks prior to study entry."

The most impressive results concerned CD4 values. The median increase in CD4
percent among IL-2 recipients was 112% at one year, compared to 18% for those on HAART alone.
In terms of absolute numbers, the mean increases were 384 cells/mm3 and 64 cells/mm3,
respectively. There was an impressive dose-response effect. Patients who received <3 MU/injection
(the protocol allowed for dose reductions if patients could not tolerate 7.5 MU) had a 39%
increase in absolute CD4 counts at one year, compared to 207% increase for those receiving
6-7.5 MU. Mean CD8 counts did not change appreciably in either group. In addition, expression
of a high-affinity receptor for IL-2 on CD4 cells increased four-fold among drug recipients
but remained essentially unchanged in the control group.

Viral load analysis showed no increase in HIV replication at one year for
patients in the IL-2 arm. Indeed, there was a small, statistically insignificant decrease
in HIV RNA among those receiving IL-2. Moreover, 67% of the IL-2 patients achieved
non-detectable viral load burdens at one year, compared to 36% of control patients.

The adverse effects of IL-2 therapy are well established. Twenty IL-2
recipients reported grade 3 or greater side effects (asthenia, fever, athralgia, myalgia,
increased LFTs, thrombophlebitis) compared to seven control patients. Despite this high
incidence of serious side effects, only one patient in the IL-2 arm withdrew because of
the toxicity of the treatment. Constitutional symptoms were managed with NSAIDs,
acetaminophen, oral hydration, and narcotics to relieve rigors. Some patients developed
antibodies to IL-2. Seven participants (3 in the IL-2 arm, one control) developed IgM
and 11 (9 in the IL-2 arm, 2 controls) developed IgG. Further lab test showed that
only three patients had sustained IgG antibodies. The clinical significance of these
antibodies is unknown, and it did not correlate with CD4 increases.

Dr. Robert L. Murphy, a member of the editorial advisory board of HIV Newsline and a co-author of this study, comments:

In 1998 immunomodulatory therapies for the treatment of HIV got a shot in
the arm, so to speak, when Carr et al. showed that CD4 counts could be increased with
subcutaneous injections of IL-2 modified with a polyethylene glycol residue. Their
protocol, which involved two injections two days apart every eight weeks, was compared
with what was then regarded as standard therapy: continuous IL-2 infusions over a five-day
period every eight weeks.

Although this group of Australian investigators found that subcutaneously
injected IL-2 was not nearly as effective as continuously infused IL-2 in boosting CD4
levels in treated patients -- the median increase was only 44 cells/mm3 in the IL-2-PEG arm,
versus 359 cells/mm3 in the IV IL-2 arm -- they were able to show an increase of 90 cells/mm3
compared with untreated controls. Moreover, they successfully demonstrated that IL-2 could
be used to upregulate immune function when it was given subcutaneously rather than by
continuous infusion -- thereby eliminating a chief stumbling block to its widespread application.

The Australian study of IL-2-PEG was conducted in patients who were receiving
dual-nucleoside antiretroviral therapy, and we wondered if patients whose viremia was maximally
suppressed on more potent regimens might respond more favorably to adjunctive therapy with
subcutaneous IL-2. Our results suggest that this is indeed the case. Moreover, we were able
to achieve impressive increases in CD4 counts in treated patients without stimulating viral
replication. In fact, our group felt that the addition of IL-2 might have potentiated the
anti-HIV effects of HAART. We will need to know how these surrogate benefits translate into
clinical outcomes. A large trial that is currently under way in this country, and two
international studies, should provide useful data regarding clinical outcomes.

Several presentations made at the recently concluded 8th Conference on
Retrovirus and Opportunistic Infections suggest that CD4 counts, not HIV/RNA levels, are
the most accurate marker of disease progression and survival. If these observations hold
up, they should spark renewed interest in drugs that enhance overall immunologic function
and support the bodys natural response to HIV infection.

Update: Treatment of Lipodystrophy

Metformin reduces insulin resistance and visceral fat deposits

A syndrome of insulin resistance, hyperlipidemia, and lipodystrophy has
been identified in patients taking protease inhibitors. These disorders may appear
individually or in combination. As with many other side effects of therapy, the risk
for increased morbidity and mortality posed by this syndrome is not knownand the need
to quantify that risk is great. Thanks to the advent of maximally suppressive
antiretroviral therapy, HIV-infected patients are living much longer than they did
a few short years ago, and the longer they live, the more crucial it becomes for
care providers to understand the long-term impact of the side effects of chronic
antiretroviral therapy.

In mid-1997 the F.D.A. issued a public health advisory in the wake of reports
of hyperglycemia and new-onset diabetes mellitus related to the use of protease inhibitors.
At that time a total of 83 cases of hyperglycemia had been reported, six of which
involved life-threatening reactions. Since that time reports of hyperglycemia, peripheral
insulin resistance, diabetes, ketoacidosis, and reduced beta-cell function have
been published. In one recent study, the rate of new-onset hyperglycemia (two serum glucose
values > 250 mg/dL or a diabetes diagnosis) was roughly 1% of nearly 1,400 clinic
patients.

Most patients with hyperglycemia also have increased concentrations of insulin,
C-peptide, proinsulin, and glucagon, but the mechanism of insulin resistance in patients taking
protease inhibitors is unknown. Potential hypotheses include direct effects of protease
inhibitors or indirect mechanisms related to changes in body fat. All patients starting
antiretroviral therapy with a drug combination that includes a protease inhibitor should
have baseline and follow-up fasting blood glucose concentrations measured, to help assess
if insulin resistance or hyperglycemia is likely to develop. Individuals who have no
diabetes or insulin resistance prior to the initiation of therapy should be counseled
to report any signs of fatigue, polydipsia, or polyuria immediately. Patients should have
a serum blood glucose test whenever these symptoms present. An oral glucose tolerance test
may elucidate glucose intolerance.

Because insulin resistance and hyperinsulinemia are significant risk factors for
coronary artery disease, patients who take protease inhibitors may be at increased risk for
CAD in addition to frank diabetes. For this reason, clinicians feel increasingly compelled to
treat hyperglycemia and hypercholesterolemia when these conditions develop in patients who are
taking protease inhibitors -- although this increases the patient's pill burden, the likelihood
of drug-drug interactions, and the prospect of additional therapy-induced toxicities.

Hadigan et al. designed a trial to test metformin, a biguanide used in the
treatment of NIDDM, in patients with insulin resistance who also had visceral adiposity.
Metformin reduces hepatic glucose production and facilitates glucose uptake by peripheral tissues.
It is associated with lower fasting glucose and hemoglobin A1C levels, as well as decreased total
cholesterol and triglycerides. The principle adverse events are GI disturbances and lactic acidosis.

The study enrolled 26 patients, all of whom had been on a stable regimen of
antiretrovirals for at least six weeks, and randomized them to receive metformin 500 mg b.i.d.
or placebo in a double-blind fashion. Subjects were "moderately overweight" and had laboratory
evidence of impaired glucose tolerance (glucose between 140-200 mg/dL at 120 minutes following
75 g oral glucose load) as well as evidence of fat redistribution. The primary outcome
measurement was a change in insulin area under the curve. Secondary outcomes included changes
in glucose AUC, lipid levels, body-mass index, diastolic blood pressure, waist-to-hip
circumference, and assessment of the ratio of visceral abdominal fat to subcutaneous abdominal
fat by CT images.

After three months, treatment with metformin was associated with significant decreases in insulin AUC
<(-20%), diastolic blood pressure, and body-mass index. Glucose AUC levels and lipid levels were not significantly different in the treatment and placebo arms of the study. Visceral abdominal fat decreased by 6% in metformin recipients and increased by 8% in placebo patients. The drug was well tolerated; there were no incidents of lactic acidosis and no patient dropped out of the study because of adverse events.

Dr. William G. Powderly, the editor-in-chief of HIV Newsline,
comments:

The finding that maximally suppressive antiretroviral therapy leads to
lipid derangements and may predispose treated patients to both diabetes and coronary
artery disease is a serious problem, and one that complicates our efforts to develop
long-term treatment strategies for HIV infection. Although this was short-term study
involving only two dozen participants, its findings are encouraging and merit further
investigation.

The work of Hadigan et al. reaffirms results obtained by Touraine and Saint-Marie in 1999. Those investigators administered metformin for two months to a group of patients who had developed abdominal fat accumulation, elevated triglycerides, and hyperinsulinemia on protease-inhibitor-based antiretroviral regimens. All of the participants experienced significant improvements in glucose tolerance and triglyceride levels compared with controls, but no changes were evident in total serum cholesterol levels between the metformin and placebo arms. Visceral abdominal fat accumulation decreased by 13.3% in the metformin group and by 5.7% in the control group. Although metformin produced intolerable GI disorders in two patients taking the drug, these data -- when combined with those of Hadigan and coworkers -- suggest that metformin may be useful in the management of patients who develop insulin resistance, hypertriglyceridemia, and visceral fat accumulation as a result of protease-inhibitor-based therapy.

Scrub Typhus and HIV Co-Infection

Conventional wisdom -- and clinical evidence -- tell us that adding other pathogens
to the mix when HIV infection is present is bad chemistry. Is it possible that another
infection could actually facilitate a host's fight against HIV? Two groups of Thai researchers,
working in collaboration with investigators at Walter Reed and St. George's Hospital in London,
believe they might have evidence to support this novel notion. Watt et al. took viral-load
measurements in HIV-positive patients diagnosed with acute scrub typhus infection, citing
earlier observations concerning scrub typhus in patients with HIV, which hinted at potentially
beneficial interactions between Orientia tsutsugamushi and HIV.

O. tsutsugamushi, the etiologic agent of scrub typhus, is a gram-negative
obligate intracellular rickettsial organism that is transmitted to humans from mites. The
infection occurs almost exclusively in Japan, Australia, and the islands of the South Pacific.
Also known as river or flood fever, scrub typhus is a febrile illness that can manifest as
myocarditis, meningoencephalitis, and pneumonitis. The site of the bite develops into a papular
lesion that may harden into an eschar. It has been reported that HIV patients with scrub
typhus do no worse than patients without HIV, which is an unusual observation concerning
infections in those already harboring HIV. Furthermore, the rate of positive blood cultures
for O. tsutsugamushi is actually lower among patients co-infected with HIV.

To study the relationship between these two pathogens, ten adults with both
infections were compared to five other individuals with HIV and either malaria or leptospirosis.
None of the patients in either group received antiretroviral therapy. Patients were examined
clinically and viral-load measurements were done on days 3, 7, 14, and 28 after admission.
Treatments administered were chloramphenicol or doxycycline for scrub typhus, quinine or
chloroquine for malaria, and penicillin for leptospirosis. Investigators documented a
statistically significant increase in HIV RNA in the five patients who did not have scrub
typhus compared to the ten with scrub typhus. Four of the ten patients with scrub typhus
experienced a dramatic drop in viral load; two became non-detectable.

HIV strains from all ten of the patients with scrub typhus were found to
be non-syncytia-inducing, a characteristic that is associated with less facile cell-to-cell
transmission of HIV. By contrast, five of seven isolates from patients without scrub typhus
were syncytia-inducing. The authors postulate that inhibition of syncytia formation may be
the mechanism by which scrub typhus suppresses HIV. They encourage further study of this phenomenon.

While no one is saying, at this point, that patients with HIV should be intentionally
coinfected with O. tsutsugamushi, it is the only organism that has been shown to possibly benefit
a host with HIV. This paper raises intriguing questions about manipulation of the immune system
in ways to optimize the host's response to HIV. The authors also note that more than 90% of
individuals with HIV infection cannot afford antiretroviral therapy and that cheaper approaches
to treatment are desperately needed.

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